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PubMed1982

In vitro antifungal activity of eugenol and vanillin against Candida albicans and Cryptococcus neoformans.

Eugenol and vanillin were examined for in vitro antifungal activity against the medically important yeasts, Candida albicans and Cryptococcus neoformans. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) were determined for each compound against 31 strains of C. albicans and 33 strains of C. neoformans. With eugenol, the mean MIC's for C. albicans and C. neoformans were 625 and 293 micrograms/mL, respectively, while the mean MFC's were 1209 and 521 micrograms/mL, respectively. With vanillin, the mean MIC's for C. albicans and C. neoformans were 1250 and 738 micrograms/mL, respectively, while the mean MFC's were 5000 and 1761 micrograms/mL, respectively. With C. albicans, inhibition and retardation of growth were similar for yeast and mycelial forms, but germ tube formation was inhibited at concentrations lower than those which inhibited growth. Short-term toxicity tests with mice using the intraperitoneal route gave maximum tolerated doses of 62.5 mg/kg for eugenol and 125 mg/kg for vanillin and excluded their use as therapeutic agents for systemic mycoses.

Candida albicans↗
PubMed1977

The influence of 5-fluorocytosine on nucleic acid synthesis in Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus.

5-Fluorocytosine (5-FC) has a rapid inhibitory effect on the synthesis of RNA and DNA in the yeast and hyphal form of Candida albicans. 5-FC has a less marked effect on the RNA and DNA content of sensitive strains of Cryptococcus neoformans and has no effect on the nucleic acid content of Aspergillus fumigatus nor of resistant strains of C. albicans and C. neoformans. 5-FC has a slower inhibitory effect on yeast cell number increase and no effect on hyphal length of hyphal phase C. albicans over a 7-h incubation period. Rapidly growing yeasts of C. albicans and C. neoformans decrease in volume and in dry weight per cell. 5-FC prevents this decrease in sensitive strains. These results have been discussed with respect to the known metabolic pathway of 5-FC, the fungistatic and fungicidal action of 5-FC and the development of resistance to 5-FC.

Aspergillus fumigatus↗
PubMed1987

Growth inhibition of Cryptococcus neoformans by human alveolar macrophages.

Macrophage cytotoxicity for Cryptococcus neoformans was investigated by culturing human alveolar macrophage (AM) with a thin-capsuled clone of C. neoformans in a polypropylene culture tube assay system. Yeast replication was quantitated by electronic particle counting after detergent lysis of AM and viability by quantitative plate counts. Under appropriate conditions, fungal replication was inhibited in the presence of human AM. This effect persisted over the 48-h time course that was evaluated. During this period, organisms in medium alone proliferated rapidly, doubling their number every 4 h. Human AM did not require endotoxin, fetal calf serum, or specific rabbit anticryptococcal antibody for fungistasis. Under these conditions, microscopic evaluation of a cytocentrifuge preparation of AM-yeast cocultures, stained by a modified Giemsa technique, revealed all the fungi to be extracellular. In the presence of 10% fresh human serum, AM phagocytized C. neoformans and exhibited fungicidal activity. Tumor necrosis factor did not affect the replication rate of the yeast. These findings suggest that there may be at least 2 mechanisms by which human AM protect against C. neoformans. One is serum-independent and extracellular and results in fungistasis, and the other is dependent on a serum factor and leads to intracellular inhibition of growth and possibly killing of the organism.

Blood↗
PubMed1985

Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide.

Cryptococcus neoformans is variably encapsulated in vitro, whereas in tissues it develops a large capsule. We observed that cells of a strain with thin capsules, when growing in a standard fungal culture medium, became heavily encapsulated when incubated in serum-free cell culture medium (Dulbecco's modified Eagle's medium [DME]). Capsule size was quantitated physically by measuring cell volume, and chemically by determining the content of a capsular monosaccharide, glucuronate. The CO2/HCO-3 couple stimulated capsule development, resulting in visible enlargement by 3 h after exposure to high CO2/HCO-3. The amount of capsule per cell was directly proportional to the total millimolar CO2/HCO-3 concentration between 24 and 2.4 mM at pH 7.35, but at constant PCO2 (40 torr) and varying [HCO-3], the cells were heavily encapsulated down to pH 6.8. Concentration of CO2/HCO-3 in the physiologic range increased elaboration of polysaccharide into the medium and slowed the cell generation time from 2 to 6 h. Four other first-passage clinical isolates were all heavily encapsulated in DME with CO2/HCO-3, but variably encapsulated in DME without CO2/HCO-3. Exposure of yeast to increased CO2/HCO-3 caused a marked reduction in complement-mediated phagocytosis by mouse macrophages. A stable clone was isolated which contained capsular polysaccharide, but lacked the CO2-inducible phenotype. This clone was avirulent for steroid-treated rabbits. Thus, the prevailing CO2 concentration in mammalian tissues may be one stimulus for capsular polysaccharide synthesis. This could serve as an adaptive mechanism favoring parasite survival in the host.

Animals↗
PubMed1977

Cryptococcosis, with emphasis on the significance of isolation of Cryptococcus neoformans from the respiratory tract.

Cryptococcus neoformans was isolated from 65 patients: 11 had meningitis, 11 had disseminated cryptococcosis without meningitis, and 43 had C neoformans isolated from the respiratory tract. Predisposing conditions and the diagnostic value of cultures from various sites and of the latex agglutination test on cerebrospinal fluid and serum are analyzed for patients with extrapulmonary disease. Nine patients had pleural effusions; the effusion was cultured in six and yielded C neoformans in four. None of 11 deaths among 43 patients with respiratory tract isolates could be attributed to cryptococosis. The 32 survivors were nor treated with antifungal agents. Twenty-six of 43 patients with respiratory isolates had various bronchopulmonary disorders, with chronic obstructive pulmonary diseases and asthma the most common (28 percent). Seven of 28 patients (25 percent) with roentgenographically detected lung lesions had carcinoma of the lung. Roentgenographic evidence of a lung lesion and C neoformans grown from the respiratory tract warrant a further search for carcinoma of the lung.

Adult↗
PubMedDate not supplied

Isolation of human fungi from soil and identification of two endemic areas of Cryptococcus neoformans and Coccidioides immitis.

The present study was carried out in two different areas of Province of Cordoba, Argentina, where there was a suspicious of endemic mycosis. The previous data were the presence of a clinical case of pulmonary cryptococcosis in one area (Alta Gracia) and the previous findings of a high incidence of coccidioidin and cryptococcin reactors in the population of the second one (Villa Dolores). In both areas soil samples for fungi were studied and Cryptococcus neoformans was found in 2/25 samples from Alta Gracia. In Villa Dolores Coccidioides immitis was isolated in 2/40 samples, and C. neoformans in 1/40 samples. Delayed hypersensitivity test with cryptococcin was determined in the population from Alta Gracia and it was found to be 5.3%. Positive cutaneous tests with coccidioidin (33.8%) and cryptococcin (31.9%) in Villa Dolores were obtained. With these findings two endemic areas of systemic mycoses in Cordoba, Argentina were delimited.

Adolescent↗
PubMed1988

Cryptococcus neoformans antibody levels in patients with AIDS.

Anti-Cryptococcus neoformans capsular polysaccharide (CPS) antibodies were measured by ELISA in patients with AIDS related complex or AIDS without a known history of cryptococcosis and in heterosexual healthy controls. Total and IgG anti-CPS antibody activity was rarely detected in patients, with mean levels lower than in controls, whereas IgM antibody activity was similar in the 3 groups. Since both humoral and cellular immunity appear to be of great importance during cryptococcosis, the inability of AIDS patients to synthetize specific IgG antibodies could impair an alternative host defence mechanism to cellular immunity.

AIDS-Related Complex↗
PubMed1987

The genetic basis of resistance to 5-fluorocytosine in Candida species and Cryptococcus neoformans.

In terms of genetically determined susceptibility to the clinical antifungal agent 5-fluorocytosine (5-FC), Candida albicans may be homozygous sensitive (FCY/FCY), homozygous resistant (fcy/fcy), or heterozygous (fcy/FCY). Although heterozygotes are only slightly resistant, they occur at significant frequency among clinical strains and carry preexisting resistance determinants which may be responsible, following homozygosis, for treatment failures. There are two resistance genes (FCY1 and FCY2) known. Resistance in fcy1/fcy1 strains was associated with decreased UMP pyrophosphorylase activity, whereas resistance in fcy2/fcy2 strains was associated with decreased cytosine deaminase activity. These results were confirmed and extended in a 19F nuclear magnetic resonance study of 5-FC uptake and metabolism in genetically defined strains. By means of hybridization via spheroplast fusion, a complementation test was devised to test allelism of resistance determinants. Resistance to 5-FC was employed as a useful genetic marker in basic studies. In tetraploid hybrids which bore appropriate fcy markers, it was possible to select for reduction in ploidy by selecting for increased resistance to 5-FC; a novel parasexual system was thus generated (2n x 2n----4n----2n). In linkage studies, the gene FCY1 was shown to be linked to the gene HIS. Reciprocal mitotic recombination was demonstrated repeatedly with fcy1 and his alleles in cis and in trans configurations and evidence for nonreciprocal recombination (mitotic gene conversion) was also obtained. In Cryptococcus neoformans, mutation in either of two genes (FCY1, FCY2) is sufficient to confer resistance. These genes behave as simple Mendelian determinants which recombine freely. Diploid C. neoformans heterozygous for resistance (FCY/fcy) provided useful strains in which to develop genetic mapping methodology based on mitotic recombination.

Candida↗
PubMed1976

In vitro and in vivo activity of 2,4-diamino-6-(2-(3,4-dichlorophenyl)acetamido) quinazoline against Cryptococcus neoformans.

The minimum inhibitory concentration of quinazoline derivative was determined by the tube dilution method for Cryptococcus neoformans, strain 184. The effect of this chemical agent on macromolecular metabolism indicated an inhibition of incorporations of labeled precursors into RNA and protein of C. neoformans. A mouse model infection with C. neoformans was established. Following this, the animals were given ip or oral doses of different concentrations of the experimental drug. Infected mice responded to ip administration of the drug in that the percentage of surviving mice increased progressively with increasing drug dosage. The curing dose 50 (CD50) was determined, based on the isolation of C. neoformans from organs of animals during or at the termination of the experiments.

Antifungal Agents↗
PubMed1975

Cryptococcus neoformans as a cause of lytic bone lesions.

Cryptococcosis is a disseminated infection of man and animals that involves many organs, especially the central nervous system. Isolated bone involvement may cause lytic bone lesions. Diagnosis may be made by pathologic sections and culture of specimens obtained through surgical biopsy. When Cryptococcus is recovered from bone, care must be taken to study other organ systems, especially the central nervous system. Isolated bone disease without meningitis is very uncommom. Intense medical therapy is necessary for treatment of meningitis; isolated osteomyelitis may respond to surgical drainage alone.

Adult↗
PubMed1975

[Contributions to the strain-specific virulence of Cryptococcus neoformans. Animal experiments with two C. neoformans-strains isolated from bird manure. Preliminary report (author's transl)].

The results briefly presented here highlight some of the observations met with during the course of a study aimed at finding out differential pathogenic behavior of the two strains of Cryptococcus neoformans i.e. W71/A117 and W2/A94 with special reference to cryptococcoma formation. Both strains were isolated from bird excreta but differed in their gross and microscopic morphology. Groups of male albino mice NMRI were separately inoculated, intramuscularly, with a comparable dose of the two strains. All the 50 animals challenged with W71/A117 developed macroscopically distinct cryptococcoma of variable size, and fatally progressive disease, involving most of the internal organs, namely, brain, heart, lung, liver, spleen and kidneys. On the contrary, only 34 of the 50 mice infected with the strain W2/A94 showed cryptococcoma formation at the site of inoculation, which were comparatively much smaller in size and gradually diminished. None of the animals, observed over a period of 93 days, died, and showed any sign of metastasis. In another series of experiment, only one instance of mortality was observed in a group of 80 mice inoculated intraperitoneally with about 2 X 10(7) viable cells of this strain. However, the fungus could be recovered, in a majority of cases, only from the brain of animals sacrificed after one month, though most of them showed no sign of sickness. The number of mice yielding positive cultures gradually decreased, and after 87 days the fungus could not be isolated from any organ. The high morbidity and mortality in mice caused by strains W71/A117 was significantly lowered when the animals were infected intramuscularly 3 months ago with the strain W2/A94. After an observation period of 61 days, 91% of the double infected animals were still alive in comparison to 23% survival among the animals challenged with the strain W71/A117 only.

Animals↗
PubMed1992

Cryptococcus albidus isolated from pigeon excreta in Taiwan.

Cryptococcus albidus (Saito) Skinner, found frequently in the air of El-Minia, Egypt; in New Zealand and Budapest, and isolated occasionally from clinical specimens, has now been recognized as the cause of human diseases. Since isolation of this fungus from pigeon droppings has not previously been reported, this first paper reports results of its drug-susceptibility testing to gentamicin and 5-fluorocytosine, as well as its fungal cell antigenic cross reactivity with C. neoformans as detected by a Latex-Crypto-Antigen Detection System (LCAS).

Animals↗
PubMed1990

Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans.

T cell-mediated immunity has been shown to play an important role in the host defense to Cryptococcus neoformans. Infections due to C. neoformans are increased in patients with AIDS who are deficient in the CD4+ subset of T lymphocytes. Thus, the effect of CD4+ (L3T4+) lymphocyte depletion on murine host defenses to C. neoformans was studied. The mAb GK 1.5 was administered to mice, and CD4+ T lymphocyte depletion was confirmed by the analysis of T cell subsets in blood, spleen, lymph node, and lung. Evidence of a functional defect was confirmed by demonstrating that the splenocytes of treated mice were unable to proliferate in response to class II incompatible spleen cells. Furthermore, delayed type hypersensitivity to C. neoformans was abrogated by CD4+ lymphocyte depletion. Mice depleted of CD4+ lymphocytes were inoculated with a virulent strain of C. neoformans by the i.v. or the intratracheal route. After i.v. inoculation of C. neoformans, the survival of mice depleted of CD4+ lymphocytes was reduced (27.8 +/- 1.8 vs 36.0 +/- 3.1 days, p less than 0.04). After intratracheal inoculation, C. neoformans disseminated from the lung to extrapulmonary organs. Dissemination occurred earlier in mice depleted of CD4+ lymphocytes compared to mice that received control antibody, and the burden of C. neoformans in extrapulmonary organs was greater in mice depleted of CD4+ lymphocytes than control mice. Surprisingly, there was no increase in the burden of C. neoformans in the lungs of CD4+ lymphocyte-depleted mice. Survival of mice inoculated with C. neoformans and depleted of CD4+ lymphocytes was reduced compared to control mice and was related to the increased rate of accumulation of organisms in the brains of treated mice. The mean survival of GK 1.5-treated mice was 34.1 +/- 0.9 days compared to control mice with a mean survival of 40.6 +/- 9 days (p less than 0.001). These data suggest that CD4+ lymphocytes play a prominent role in the host defense of infections due to C. neoformans, that CD4+ lymphocytes are required in extrapulmonary organs for optimal clearance of C. neoformans and that CD4+ lymphocytes are critical for survival of mice infected with C. neoformans.

Animals↗
PubMed1988

Induction of antigen-specific suppression by circulating Cryptococcus neoformans antigen.

Immunoaffinity chromatography of sera from mice infected with Cryptococcus neoformans (Inf-MS) on a column with rabbit anti-cryptococcal antibody as the ligand resulted in the adsorption of the component(s) that induce suppression of the cryptococcal delayed-type hypersensitivity (DTH) response. In contrast, immunoaffinity chromatography of Inf-MS on columns coupled with cryptococcal antigen or goat anti-mouse IgM, IgG, and IgA did not adsorb the suppressive component(s). Quantification of cryptococcal antigen and anti-cryptococcal antibody in Inf-MS and column fractions established a direct correlation between cryptococcal antigen levels and suppressive activity; no correlation was observed between anti-cryptococcal antibody levels and suppressive activity. The suppression induced by Inf-MS was shown to be specific in that suppressive sera did not affect the induction of DTH responses to Listeria monocytogenes or dinitrofluorobenzene. These collective results provide evidence that cryptococcal antigen is the component in Inf-MS that induces antigen-specific suppression of the cell-mediated immune response to C. neoformans.

Animals↗
PubMed1989

Fungicidal activity of IFN-gamma-activated macrophages. Extracellular killing of Cryptococcus neoformans.

Cryptococcus neoformans is an encapsulated yeast-form fungus which causes pulmonary and meningeal infections preferentially in the immunocompromised host. It is thought that cell-mediated immunity is important for acquired resistance against cryptococcosis with activated macrophages as the final effector cells. However, specific polysaccharides in the capsule of C. neoformans protect the fungus from adherence to phagocytes and from subsequent phagocytosis. We have studied extracellular killing of C. neoformans by IFN-gamma-activated macrophages and their products. Murine bone marrow-derived macrophages stimulated with rIFN-gamma for 24 h were able to effectively suppress the growth of C. neoformans and the effect of IFN-gamma was augmented by LPS. Killing of C. neoformans was also achieved by cell-free supernatants from bone marrow-derived macrophages stimulated with IFN-gamma plus LPS. Our results indicate that killing of C. neoformans by activated macrophages is independent from toxic oxygen radicals and mediated by secreted protein(s) of apparent molecular mass of 15 and 30 kDa. These findings indicate that activated macrophages play a major role in host defense, although the fungus resists phagocytosis and remains in the extracellular milieu.

Animals↗
PubMed1989

Paradoxical role of capsule in murine bronchoalveolar macrophage-mediated killing of Cryptococcus neoformans.

Infections with the encapsulated fungus Cryptococcus neoformans are usually acquired via inhalation, and the presence of a capsule has been identified as a virulence factor. Therefore, we studied murine bronchoalveolar macrophage (BAM)-mediated killing and phagocytosis of encapsulated and acapsular strains of C. neoformans. After 2 h, BAM killed encapsulated strains CN52 and MP415 more readily than acapsular strains CN602 and CAP67 (54.9 and 36.2% vs 26.1 and 6.7%, respectively, p less than 0.001). Pre-incubating CN602 with purified capsular polysaccharide increased killing to 42.7% (p = 0.04). Significantly greater killing of the encapsulated strains also occurred in vivo. BAM-mediated killing of CN52 appeared to proceed by non-oxidative mechanisms, as BAM released minimal amounts of H2O2 after stimulation with CN52, and killing was not reduced by inhibitors or scavengers of the respiratory burst. The association between encapsulation and susceptibility to BAM fungicidal effects was not attributable to differences in yeast ingestion. Using the same low ratio of organisms to BAM as in the killing assay, greater than 95% of both CN52 and CN602 were phagocytosed. However, BAM phagocytosed significantly greater numbers of acapsular CN602 when incubated with a higher inoculum. Phagocytosis and killing of CN52 and CN602 required fresh serum as a source of C. Phagocytosis of CN52, but not CN602, was profoundly inhibited if BAM were plated on surfaces coated with mAb against the C3bR (CR1). mAb against the iC3b receptor (CR3) did not affect phagocytosis of either strain. These data demonstrate the innate ability of BAM to preferentially kill, by apparently non-oxidative mechanisms, an encapsulated as opposed to acapsular organism. Inasmuch as different receptors appear involved in phagocytosis of encapsulated versus acapsular C. neoformans, the disparity in killing may result from the greater ability of receptors mediating uptake of encapsulated organisms to trigger the antimicrobial armamentarium of the BAM.

Administration, Intranasal↗
PubMed1989

Phagocytosis of Cryptococcus neoformans by rat alveolar macrophages.

A radiolabeling method was developed to investigate the interaction in vitro between Cryptococcus neoformans and Lewis rat alveolar macrophages (AM phi). AM phi were harvested by lung lavage, monolayers of adherent cells were established in wells of microtiter plates and [51Cr]-labeled yeast cells were added to the monolayers. After removal of extracellular yeasts, the adherent radioactivity associated with the AM phi was directly proportional both to the number of yeasts added and to the number of yeasts per AM phi as determined by microscopic examination of Giemsa-stained monolayers. Phagocytosis (attachment and/or ingestion) of radiolabeled C. neoformans by AM phi was a sensitive, quantitative and reproducible assay for the evaluation of the AM phi-C. neoformans interaction. AM phi were able to phagocytose encapsulated strains of C. neoformans. The extent of phagocytosis was inversely related to the capsule size. Normal rat serum (NRS) was an excellent source of opsonins for the ingestion. Inactivation of serum complement or depletion of C3 by affinity chromatography removed most of the opsonic activity of NRS. Specific antibodies against C. neoformans did not increase phagocytosis.

Agglutination Tests↗
PubMed1989

Killing of Cryptococcus neoformans by rat alveolar macrophages.

The addition of [51Cr]-labeled yeast cells of Cryptococcus neoformans to monolayers of Lewis rat alveolar macrophages (AM phi) provided a sensitive and reproducible in vitro assay of phagocytosis. AM phi and yeast cells were incubated in 10% (v:v) normal rat serum for 1 h, non-AM phi associated yeast cells were removed and the AM phi-associated radioactivity (phagocytosis) determined. Replicate wells were replenished with fresh medium and reincubated. At different times, yeast-AM phi monolayers were treated with a non-cryptococcocidal mixture of DNAse and sodium deoxycholate to release the yeast cells from the AM phi. The fate of the yeast cells was critically evaluated by [51Cr]-release and viable plate counts. Killing was detected by plate counts within an hour following phagocytosis and did not increase significantly during the next 5 h. Strains of C. neoformans with small, medium, or large capsules varied in their susceptibility to killing from 10% to 95% but susceptibility to killing was not directly related to capsule size and the extent of phagocytosis. Release of 51Cr did not correlate with viability as determined by culture. The 51Cr was associated with two pools in the yeast cells; one, representing 15-20% of the radiolabel, was easily released and was probably bound to low molecular weight compounds in the cytoplasm. The majority of label was tightly bound to the particulate alkali-soluble cell wall fraction.

Animals↗